Expert Critique

Lung cancer is the leading cause of cancer death, which is mostly due to diagnosis at advanced stages and the only modest responses to current antineoplastic agents used against it despite decades of research. The modest survival benefits with the current chemotherapy regimens have led to more vigorous research to create the new targeted agents against non-small cell lung cancer (NSCLC). Among these, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) played a significant role in increasing antitumor activity in advanced NSCLC.

Erlotinib is one of the main targeted therapies against EGFR-mutated NSCLC. Many trials have shown the superior overall survival and improved quality of life with erlotinib compared with conventional chemotherapy and best supportive care. The convenience of oral availability and the lower incidence of hematologic adverse effects made this an attractive option for advanced NSCLC patients. However, careful selection of the patient population to be treated and the EGFR-mutation status had an impact on predicting the effectiveness and response to EGFR TKIs.

Erlotinib has a number of effects on our healthcare system: It is an oral agent, which can be self-administered. It does not require long hours of intravenous infusion in a monitored setting. It has a more manageable side effect profile with less hematologic adverse events compared with conventional chemotherapy, which precludes long hours of blood product transfusions and/or hospitalizations for management of other grade 4 toxicities.

Erlotinib is overall more convenient for both the patient and healthcare providers. When all of these factors are considered, it is reasonable to consider erlotinib as a more viable option both financially and therapeutically. It yields more cost-effective clinical benefit in a select patient population -- especially the elderly who cannot tolerate conventional chemotherapy. Still, more clinically relevant studies focusing on cost effectiveness need to be conducted to further investigate and demonstrate its actual impact on the U.S. healthcare system.

Full Critique

The inhibition of epidermal growth factor receptor (EGFR) has become an important target in the treatment of patients with advanced non-small cell lung cancer (NSCLC), and one of the main weapons against EGFR-mutated NSCLC is erlotinib (Tarceva), the small molecular agent that targets the tyrosine kinase domain of EGFR.

Plenty of research has confirmed the clinical value of erlotinib as first-line treatment in NSCLC, but what about the costs of this treatment regimen? Recent data show that erlotinib may be more cost effective as a first-line treatment than standard chemotherapy for patients with EGFR-mutated advanced NSCLC.

One group of researchers, led by Alain Vergnenegre, MD, PhD, of Limoges University Hospital in France, went so far as to state that "in the first-line setting, erlotinib dominates chemotherapy in patients with EGFR-mutated NSCLC in a white population."

His group reviewed the results of an open-label, phase III clinical trial performed in France, Italy, and Spain that compared first-line therapy with erlotinib versus standard chemotherapy in patients with EGFR-mutated NSCLC. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival and tolerability.

The study assessed the costs of the drugs and their administration on the basis of national tariffs for diagnosis-related groups and on national fees for ambulatory care.

The results showed that erlotinib yielded more quality-of-life years (QALYs) than chemotherapy did, and saved costs in all three countries analyzed (U.S. dollar amounts approximate):

Spain: 7,807 Euros ($8,817)

Italy: 17,311 Euros ($19,549)

France: 19,364 Euros ($21,868)

The mean life-years were the same for both arms in all three countries -- specifically 1.873 for erlotinib and 1.878 for standard chemotherapy.

"The largest cost savings were found in France, but the gain in QALYs and mean life-years did not differ across the countries," the researchers noted.

Regarding study limitations, though, the data examined were only for patients managed in a clinical trial, thus limiting the size of the cohort, and could differ from the general NSCLC population. Also, only adverse events affecting more than 3% of the patients were included in the trial as a cost element; however, adverse events affecting less than 3% of patients may require expensive treatments. Lastly, Vergnenegre and coauthors observed that health management costs will vary in other health systems.

In another study, Ifetkhar Khan, PhD, of University College London, and colleagues found that erlotinib has about an 80% chance of being cost effective at thresholds between ₤50,000 to ₤60,000 ($71,023 to $85,227) among elderly NSCLC patients unfit for chemotherapy. "Erlotinib is potentially cost-effective for this population, for which few treatment options apart from best supportive care are available," the researchers pointed out.

They looked at a patient population of 670 newly diagnosed, pathologically confirmed, stage IIIb-IV, NSCLC patients deemed unsuitable for chemotherapy based on their Eastern Cooperative Oncology Group (ECOG) performance status (PS ≥2) or medical comorbidities, such as renal impairment.

Patients received 150 mg of erlotinib or placebo until disease progression, and were followed until progression or death. The primary endpoint was overall survival, and progression-free survival and health-related quality of life were secondary endpoints.

The erlotinib group had an overall survival of more than 3 months as well as an improvement in quality of life, leading the authors to conclude that 15% to 40% of the cohort studied would have a cost-effective clinical benefit with the therapy.

The researchers observed that a low EGFR mutation rate (5%) in their study population was insufficient to establish the cost effectiveness of erlotinib for this group.

In the third study, Christos Chouaid, MD, of Hopital St-Antoine in Paris, and colleagues reported that in fit elderly patients with NSCLC, erlotinib followed by chemotherapy was more cost effective compared with chemotherapy followed by erlotinib.

The study found that median overall survival, QALY, and total costs for an erlotinib-first strategy were 7.1 months, 0.51, and 27,734 Euros ($31,346), respectively, compared with 9.4 months, 0.52, and 31,688 Euros ($35,776), respectively, for the chemotherapy-first strategy.

Although costs were lower with an erlotinib-first strategy, the researchers reported that there was no significant difference in patient outcomes between that strategy and the chemotherapy-first strategy.

They noted that the analysis was limited to direct lung cancer-related medical costs and that indirect costs, such as lost productivity and caregiver salaries, were not included. In addition, EGFR status was not known in the patient population.

While all 3 studies came out in favor of erlotinib in this patient population, more work is needed -- both in and outside the clinical research realm -- to bolster the agent's role, particularly in the era of escalating healthcare costs, Chouaid and Vergnenegre -- along with Isabelle Borget of Institut Gustave-Roussy -- noted in a letter to the editor in the Journal of Clinical Oncology.

"Clinically relevant cost-effectiveness studies are necessary, but at a national level we also need to have a larger debate involving public health organizations and pharmaceutical companies as well as clinicians and patients to challenge the increase in the cost of treatment for the patient with cancer," they wrote.

Vergnenegre and co-authors disclosed no relevant relationships with industry.

The study by Khan's group was supported by Cancer Research U.K., with erlotinib provided by Roche Pharmaceuticals at no cost. Khan and coauthors disclosed no relevant relationships with industry; one co-author disclosed support from the University College London Hospital Biomedical Research Centre.

The study by Chouaid's group was supported by Limoges University Hospital and F. Hoffmann-La Roche. Chouaid disclosed relevant relationships with Roche Pharmaceuticals, Amgen, GlaxSmithKline, Astra Zeneca, and Lilly, and one co-author disclosed relevant relationships with Roche Pharmaceuticals, Astra Zeneca, and Lilly.

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